We have been engaged in experimental studies on the electrophysiologic mechanisms of cardiac arrhythmias under the Lethal Arrhythmias program. This grant application is made to continue our on-going basic research projects on cardiac arrhythmias. There have been two basic concepts forwarded to explain the genesis of cardiac arrhythmias, i.e., enhanced automaticity and re-entry. The exact nature of these electrical abnormalities responsible for different types of arrhythmias is not yet completely clear. We propose to further investigate electrophysiologic mechanisms of various arrhythmias, utilizing the techniques of recording extracellular activity in the heart in situ and recording transmembrane potentials with microelectrodes in the isolated heart tissue. The proposed projects will involve experimental studies on dogs on the effects of exposure of cardiac tissues to abnormal conditions, such as myocardial ischemia and infarction, abnormal ionic concentrations, digitalis, antiarrhythmic agents and autonomic neurotransmitters. The particular emphasis will be placed on the mechanism of life-threatening and fatal ventricular arrhythmias associated with myocardial ischemia and infarction. The better understanding of the electrophysiologic mechanisms will lead to improved methods of treatment and prevention of these lethal arrhythmias.